Dr. Charles Brenner is the world's foremost authority on Nicotinamide Riboside. He describes the differences between the various NAD precursors in this Seeking Alpha interview and in recent podcasts with Dave Asprey, Ben Greenfield, Natalie Eva Marie, and explains how the various NAD precursors help cells create NAD.

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The basic idea is this: NAD allows the mitochondria in our cells to power all the processes that keep us alive. But NAD levels can be depressed by outside stresses, such as drinking alcohol, overeating, sun exposure, oxidative stress, even very loud noises, as well as neurodegenerative diseases and heart disease.

 

When we are younger, our NAD levels are high, and our cells can resist and recover quickly from stresses. But as we age, NAD levels naturally drop, and our cells become more and more susceptible to damage.

 

NAD replenishment can limit the risk of harm, help our DNA repair itself, and even help our bodies recover from some of the damage.​

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We experience the damage resulting from NAD deficiencies as the various symptoms and diseases of aging, which is why NAD precursors summon images of a "Fountain of Youth." The underlying science, of course, isn't about making your body younger, but simply making sure that our cells have access to as much energy as they did when we were younger, so they can function as effectively as they did when they were younger -- but the result certainly seems to have anti-aging aspects.

 

So we'll look at each of the NAD precursors to understand the pros and cons, and their relative ability to replenish our NAD levels so that our cells can function at full power, like when we were young.

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Niacin or Nicotinic Acid (NA)

Niacin was discovered in the 1930's. It's the "Vitamin B-3" that is in fortified milk and flour. Just a dash of Niacin -- 15 milligrams -- is enough to prevent Pellagra, which is potentially fatal condition that affected millions of Americans and killed hundreds of thousands before we started adding Niacin to the food supply; now Pellagra is basically unheard of.

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At high doses, like 1,000 milligrams, Niacin has other beneficial effects. Niacin can lower your blood cholesteral and raise your HDL levels.

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And Niacin is familiar, safe, and inexpensive.  What's not to love?

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First, Niacin causes uncomfortable flushing in most people.

 

Second, Niacin only functions as an NAD precursor in some types of cells in the body, including the liver, but excluding neurons, brain cells and skeletal muscle cells, which are among the most important for protecting.

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So take as much Niacin as you are comfortable taking, but Niacin can't provide the full range of anti-aging benefits, and specifically cannot help with cognitive health.

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Nicotinamide or Niacinamide (NAM)

Nicotinamide, aka Niacinamide, like Niacin, was discovered in the 1930's, and also wards off Pellagra. 

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Nicotinamide is better than Niacin in some respects, because it doesn't cause flushing, and it is available as an NAD precursor to all tissues. It is also well-known and inexpensive. What's not to love?

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Nicotinamide has two main problems.

 

First, Nicotinamide inhibits sirtuins.

 

Sirtuins are a type of protein that manages many cellular processes, and sirtuins are critical for cell maintenance and DNA repair. The reason we are trying to energize our cells is not only so they can defend themselves, but also so they can repair themselves. 

 

One of the problems with NAD deficiency is that it prevents sirtuins from functioning, because sirtuins, like mitochondria, rely on NAD for energy.

 

So if we increase NAD in a manner that STILL inhibits sirtuin activity, which is what NAM does, that represents a pyrrhic victory at best, because we replenish NAD in such a way that we do not get the full benefits of replenishing NAD. Our cells have more energy, but they cannot use that energy to perform the most important reparative functions.​

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Second, Nicotinamide grows less effective as we age. The older we get, the less NAD gets generated from Nicotinamide.

 

Worse still, Nicotinamide becomes less available in cases of inflammation or obesity, which is exactly the kind of stressful moment when cells need MORE NAD.

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Finally, Nicotinamide even lacks Niacin's cholesterol-reducing effects, and in this study Nicotinamide actually worsened neurodegeneration in a Parkinsons Disease model.

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So at first Nicotinamide looks like a good option, but in fact Nicotinamide does not deliver the benefits we are looking for, and it doesn't even replenish NAD efficiently when we need it most, which is as we age and when we endure metabolic stress.

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Nicotinamide Riboside (NR)

Until 2004, NR was a little-known and mostly-unloved molecule – an unimportant cousin of Vitamin B3. But that all changed when a Genetics professor at Dartmouth College, Dr. Charles Brenner, discovered a previously unknown pathway by which cells could use NR to create NAD.

 

The NR Kinase pathways are turned on in every cell. And the NR Kinase 2 pathway becomes especially active when cells are under stress. In other words, stressed or damaged cells are actively looking for NR that they can turn into NAD to help repair themselves.

 

NR is a natural substance. It can be found in trace amounts in milk. And just as Niacin prevents Pellagra, NR can prevent NAD deficits.

 

But you would have to drink 75 gallons of milk to get a recommended dose of NR -- even more if you are older or stressed. So, as with Niacin, NR supplementation is necessary.

 

But unlike Niacin, NR does not cause flushing, and NR is available to all cells.

 

And unlike Nicotinamide, NR does not inhibit sirtuin activity and does not decline in effectiveness with age or stress -- if anything, NR becomes more available in times of stress.

 

So that's why NR is considered the most efficient and effective of the NAD precursors: It works well, it works in every cell, and it keeps working when you get older or are stressed.

 

NR is not as well-studied as Niacin, but 150+ studies are underway, and among those that have been completed are a randomized, double-blind, placebo-controlled cross-over human study showing that NR is both safe to take and effectively increases NAD levels.

 

What's not to love? 

 

The price -- it costs about a dollar a day, either from amazon or directly from the manufacturer, which is about 20x more than Niacin, but still totally worth it for the health benefits. Most of the medications for EVERY condition that NR supplementation prevents or cures costs more than $1 per day. And for some of those conditions, there are no cures.

 

Because NR is sold as a health supplement, and not a regulated pharmaceutical, its manufacturers are prohibited from saying that it is intended to treat, cure, or prevent any disease. But the emerging scientific evidence shows that NR replenishment is effective in animals, and safe in humans, so why let let lab mice have all the fun?

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The only licensed form of NR commercially available is called "Niagen," which is actually NR-chloride. The chloride is a salt that makes Niagen stable at room temperature and gives it a long shelf-life.

 

Nicotinamide Mononucleotide (NMN)

Nicotinamide Mononucleotide, or NMN, is actually just NR with an extra molecule attached -- a "phosphate". That phosphate addition makes NMN too big to enter cells and replenish the NAD.

 

BUT, if the phosphate gets stripped off, then the NMN turns into NR and ought to function in the many good ways that NR does -- because then it IS in fact NR.

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Using NMN as an NR precursor to generate NR that then becomes available to all cells to replenish NAD in theory ought to work fine, and early tests with mice suggest that it does work fine. But there are two things not to love:

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The first problem is that (1) our bodies must go to the trouble of stripping off the phosphates to get to the NR, and (2) then getting rid of the all the phosphates -- although that is the kind of thing our kidneys are equipped to handle and do in fact handle. So the overall process might be a little slower or less efficient, but could well deliver the same results. [This article points to evidence suggesting that NMN may be able to enter some types of cells intact, but this rebuttal article disputes the evidence that NMN can enter the cells directly.]

 

A more practical problem with NMN is that there is not currently a good way to manufacture NMN inexpensively and at scale. As a result, if you look at the most popular NMN on Amazon, the cost at first appears similar to NR on Amazon or NR directly from the only licensed manufacturer. But look closer, and you'll see that with the NMN sometimes you get half as much for about the same price -- thirty 125mg capsules instead of sixty -- which means the NMN costs twice as much. Although a bulk purchase of NMN might bring the prices closer.

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And in truth it might actually cost MORE than twice as much, because a part of every NMN capsule is a phosphate that's just going to be excreted by our kidneys.

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Worse, the science is far behind on NMN, so although it looks like NMN is comparable in terms of efficacy and safety (although this recent study suggests that NMN may be harmful in some situations where NR is not), we won't know as much about it as we know about NR.

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Even worse still, even Dr. Sinclair concedes that NMN degrades if it is not refrigerated, which means that NMN purchased online is not likely to arrive intact, especially if it has sat in a warehouse at length.

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So given that NMN just gets turned into NR anyway, and costs twice as much as straight NR, and there is no research that says NMN is better than NR, and no particular reason to expect the NMN research to show superior results -- if anything, the precursor conversions are more likely to cause problems as to create benefits -- there is currently no good reason to favor NMN over NR. [Update: 1/2018] And this study published on November 15, 2018 suggests that NR may be five times more effective than NMN at driving up intracellular NAD in skeletal muscles.

 

In fact the smart consumer would jump at the opportunity to pay half as much or get twice as much by choosing NR over NMN.

 

Choosing NR over NMN seems like a no-brainer, at least until the retail price of NMN changes or the research suggests that NMN has some important advantage over NR, which as of today no research does.